Trigonitis refers to the nonkeratinizing squamous metaplastic changes in the bladder trigone. The trigone is the triangular area of the bladder bound by the ureteral orifices and the internal urethral sphincter, which is normally lined by urothelium, a type of transitional epithelial tissue.[1] This entity was first described by Heymann in 1905 as cystitis trigoni[2] and was subsequently described by Cifuentes as a true trigonal membrane.[3] It is also referred to in the literature as pseudomembranous trigonitis or vaginal metaplasia.
Squamous metaplasia of the trigone occurs almost exclusively in women of childbearing age. It is almost nonexistent in children. Although the exact cause of trigonitis is unknown, the condition usually occurs in response to an irritative (eg, chronic indwelling catheter) or infectious process.
Trigonitis is a benign lesion without malignant potential. It does not require follow-up cystoscopy. However, it should be distinguished from keratinizing squamous metaplasia (leukoplakia), which does require follow-up.
For patient education resources, visit Cancer Center. Also, see Cystoscopy (which is necessary to diagnose trigonitis) and Bladder Cancer.
Trigonitis, despite its name suggestive of inflammation, is a metaplastic process. Although the precise underlying cause is not known, squamous metaplasia in the bladder usually occurs in response to an irritative (eg, chronic indwelling catheter) or infectious process.
Because nonkeratinizing squamous metaplasia is most commonly found in adult women of childbearing age, a hormonal influence is posited. In a study of bladder biopsies performed in women with pseudomembranous trigonitis and women who underwent cystoscopy for staging gynecological cancer, estrogen and progesterone receptors were found in the trigone in association with squamous metaplastic changes.[4] In a more extensive mapping of estrogen and progesterone receptors in the female lower urinary tract, both were found in squamous epithelial tissue, including the transitional cell epithelium in the trigone and proximal urethra that has undergone squamous metaplastic change.[5]
In the first known case report of a 16-year-old boy with Klinefelter syndrome diagnosed with pseudomembranous trigonitis, the findings of raised estrogen levels in conjunction with increased expression of estrogen receptors in the trigone area of the biopsy suggest that estrogen could be an etiological driver, much like the association of Klinefelter syndrome with estrogen-driven cancers such as breast cancer.[6]
However, whether hormonal influences lead to squamous metaplasia is unclear. Others have suggested that squamous cell metaplasia is not associated with increased estrogen activity.[7, 8] Kvist et al did not find estrogen receptors in 36 historically collected samples of squamous metaplasia of the bladder urothelium, although the authors posited that relatively few existing receptors might have been destroyed in the tissue preparation process.[8]
Instead, other explanations focus on the potential role of chronic inflammation and/or a deficient urothelium. In one autopsy study of adult women, histological evidence of chronic inflammation was found significantly more often in bladders with squamous metaplasia. The authors suggest that squamous metaplasia is not a consequence of chronic inflammation but rather that its surface characteristics may predispose to chronic infection.[9]
Squamous metaplasia is observed over edematous or inflamed lamina propria.[10] Electron microscopy of the keratinizing variant has demonstrated that squamous metaplastic cells lack the tight junctions seen in normal transitional epithelial cells, which might allow urine to permeate the subepithelial layers and result in ongoing inflammation.[11]
Bacterial cystitis has been associated with the development of trigonitis in cases of recurrent urinary tract infections. The interstitial cystitis literature suggests that the mucosal coating of the bladder surface, also known as the glycosaminoglycan (GAG) layer, plays an important role in preventing the permeability of urinary solutes into the bladder wall.[12] Restriction of the characteristic lesion to the trigone of the bladder is possibly due to the estrogenic effect. This could be explained by the fact that the trigone is anatomically and embryologically distinct from the remainder of the bladder, thereby allowing the trigonal epithelium to respond to estrogenic stimulation.[13]
Defects in this protective mechanism, or injuries resulting from chronic irritation or recurrent infections, may result in chronic inflammatory changes leading to metaplasia. However, not all individuals with squamous metaplasia are symptomatic, and not all symptomatic patients have squamous metaplasia.
The frequency of trigonitis differs according to various reports. Nonkeratinizing squamous metaplasia of the bladder neck and trigone can be seen in 50-70% of premenopausal women and is considered a normal variant.[7, 11] When Wiener et al examined 100 grossly normal bladders at autopsy, they found squamous metaplasia in 46% of premenopausal and postmenopausal women and 7% of men.[14] Another autopsy study of 106 women who died from nongenitourinary causes found that 72% exhibited squamous metaplasia in the trigone.[9] Other reports suggest that trigonitis occurs in approximately 40% of adult women and approximately 5% of men.[15] It may also be seen in men receiving hormonal therapy for prostate cancer.[16]
Squamous metaplasia of the trigone occurs almost exclusively in women of childbearing age. It is almost nonexistent in children.
The prognosis for patients with nonkeratinizing squamous metaplasia of the bladder is excellent.
Trigonitis, or nonkeratinizing squamous metaplasia, is considered benign and without malignant potential. However, it must be differentiated from keratinizing squamous metaplasia, also known as leukoplakia, which is characterized by downward growth of rete pegs (acanthosis), cellular atypia, and dysplasia. Leukoplakia is believed to be a response of the normal urothelium to noxious stimuli and is generally considered a premalignant lesion that may progress to squamous cell carcinoma in as many as 20% of cases.[1] See the image below.
Individuals with squamous metaplastic changes in the bladder may be asymptomatic or present with irritative voiding symptoms (eg, frequency, urgency, dysuria), recurrent urinary tract infections (UTIs), hematuria, or pelvic pain. Specific attention should be directed at establishing the presence and pattern of specific voiding symptoms.
Because trigonitis is a cystoscopic finding, a physical examination is unlikely to identify this lesion. However, a complete genitourinary exam may be helpful in ruling out other causes of symptoms that bring the patient to medical attention.
Cystoscopy is necessary to make the diagnosis of trigonitis. Urinalysis and urine culture can be performed to exclude infection, as is often done prior to cystoscopy. Imaging studies are not necessary to confirm the diagnosis.
In one study of transabdominal ultrasonography, women with asymptomatic, cystoscopically-confirmed trigonitis had thickening of the muscosa around the bladder neck when compared with women who had cystoscopically normal bladders.[17]
Cystoscopy is necessary to make the diagnosis. Grossly, the lesion appears as a glistening, fluffy white patch of bladder mucosa with well-defined borders. See the image below.
View Image
Cystoscopic appearance of trigonitis as a well-defined white area overlying the trigone.
Usually recognized by its distinct gross appearance and typical location in the trigone, biopsy of the lesion is usually deferred. However, biopsy may be warranted in males, females with hematuria, pediatric patients, or if the lesion is outside of the trigone because such lesions are more likely to be keratinizing and potentially precancerous.
Nonkeratinizing squamous metaplasia of the trigone is composed of stratified squamous epithelium that often contains abundant glycogen. The basal cell layer has prominent nuclei with condensed chromatin and nucleoli. The surface cells are linked by desmosomes and are longitudinally oriented. Jost et al found the mitotic index within these lesions to be 0.17%, higher than the expected value of 0%.[18] See the image below.
View Image
Nonkeratinizing squamous metaplasia. Stratified squamous metaplasia is usually seen in the bladder neck and trigone. Note the lack of densely eosinoph....
Asymptomatic patients do not require treatment. A urologist may be consulted in symptomatic cases. Several treatment approaches have been tried in patients with symptomatic trigonitis, including medications and surgery. Because it presents a constant source of irritation, chronic indwelling instrumentation of the bladder should be discouraged if better alternatives for bladder drainage are feasible.
Treatment with doxycycline proved effective in a study of 103 women with cystoscopially confirmed trigonitis who had presented with persistent urinary frequency, chronic urethral and/or pelvic pain associated with dyspareunia, and/or a history of recurrent urinary tract infections (UTIs). In addition to vaginal tablets to eradicate microbial reservoirs, the women received doxycycline at 100 mg twice daily for 2 weeks, followed by 100 mg daily for 2 weeks. Sexual partners were also treated with doxycycline 100 mg twice daily for 2 weeks, and the use of condoms was recommended during the entire treatment period. Following the treatment, 30% of patients considered themselves cured and 41% reported symptom improvement. On follow-up cystoscopy in 31 patients, trigonitis was completely resolved in 8 cases and diminished in 12 cases.[19]
An ongoing randomized trial in Europe is comparing oral clarithromycin 500 mg daily and intravesical sodium hyaluronate instillation at 40 mg weekly (Cystistat) in patients with trigonitis. Sodium hyaluronate is a derivative of hyaluronic acid that replaces the deficientglycosaminoglycan (GAG layer in the bladder wall.[15] However, intravesical sodium hyaluronate is not approved by the US Food and Drug Administration (FDA).
Endoscopic treatment with an Nd:YAG laser was attempted in women with urethral syndrome and biopsy-confirmed squamous metaplasia of the bladder refractory to medical treatment. Patients (n=62) were randomized to end-firing or side-firing Nd:YAG laser treatment at 30 W. Although results, as assessed by the Urogenital Distress Inventory short form (UDI-6), were significantly better in the side-firing group, follow-up cystoscopy and biopsy found that squamous metaplastic lesions were no longer present in patients of either group with symptom improvement, but white lesions in the bladder neck and trigone were seen in patients whose symptoms were unchanged or worsened.[20]
In a retrospective study of 33 women with longstanding recurrent UTIs refractory to antibiotic treatment who underwent cystoscopy with fulguration of trigonitis (CFT), 76% had a complete cystoscopic resolution of the trigonal lesions at 6 months postoperatively. The patients with complete resolution had a significantly decreased need for antibiotic treatment for UTI-related symptoms and/or positive urine cultures compared with the group with residual trigonitis following CFT.[21]
Medication is not necessary in asymptomatic patients with trigonitis. Please refer to the Treatment section for agents tried in patients with symptomatic trigonitis.
Wellman W Cheung, MD, FACS, Clinical Professor, Department of Urology and Department of Obstetrics and Gynecology, State University of New York Downstate Medical School
Disclosure: Received grant/research funds from Astallas for pi.
Coauthor(s)
Sophia Kawa Chiu, MD, MA, MSc, Resident Physician, Department of Urology, State University of New York Downstate Medical Center
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Edward David Kim, MD, FACS, Professor of Surgery, Division of Urology, University of Tennessee Graduate School of Medicine; Consulting Staff, University of Tennessee Medical Center
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Endo.
Additional Contributors
Leonard Gabriel Gomella, MD, FACS, The Bernard W Godwin Professor of Prostate Cancer Chairman, Department of Urology, Associate Director of Clinical Affairs, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University
Disclosure: Received consulting fee from GSK for consulting; Received honoraria from Astra Zeneca for speaking and teaching; Received consulting fee from Watson Pharmaceuticals for consulting.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Scott Rutchik, MD, to the development and writing of this article.
References
Chai TC, Birder LA. Physiology and Pharmacology of the Bladder and Urethra. Wein AJ, Kavoussi LR, Partin AW, Peters CA, eds. Campbell-Walsh Urology. 11th ed. Philadelphia, PA: Elsevier; 2016. 1631-84.
Heymann A. Die cystitis trigoni der frau. Zentralbl Kr Harn Sex. 1905. 16:422-33.
Cifuentes L. Epithelium of vaginal type in the female trigone: the clinical problem of trigonitis. J Urol. 1947. 57:1028-37.
Murali K. Ankem MK, Grotas, AB, Shurtleff B, DiPiazza D, Barnard N, et al. Nonkeratinizing Squamous Metaplasia of the Bladder in Children. Available at http://www.medscape.com/viewarticle/447776_2. 2002; Accessed: February 16, 2018.
Stavropoulos M, Papatsoris AG, Konstantinidis C, and Chrisofos M. Pseudomembranous Trigonitis: A Common but Underrecognized Urological Entity. Advances in Urology. 2010. 2010:
American Urological Association. Squamous Metaplasia. www.auanet.org. Available at http://www.auanet.org/education/auauniversity/education-products-and-resources/pathology-for-urologists/urinary-bladder/non-neoplastic-lesions/squamous-metaplasia. Accessed: February 16, 2018.
Hussain SA, Alhalabi F, and Zimmern PE. Long-term efficacy of fulguration of trigonitis for recurrent urinary tract infections in women. Urol Sci. September 2015. 26(3):197-201.
Murphy WM. Diseases of the urinary bladder, urethra, ureters, and renal pelves: squamous metaplasia. Urological Pathology. 1997. 60-2.
Keratinizing squamous metaplasia of the bladder.
Cystoscopic appearance of trigonitis as a well-defined white area overlying the trigone.
Nonkeratinizing squamous metaplasia. Stratified squamous metaplasia is usually seen in the bladder neck and trigone. Note the lack of densely eosinophilic layer, representing keratin, at the luminal side, in contrast with the earlier figure.
Keratinizing squamous metaplasia of the bladder.
Cystoscopic appearance of trigonitis as a well-defined white area overlying the trigone.
Nonkeratinizing squamous metaplasia. Stratified squamous metaplasia is usually seen in the bladder neck and trigone. Note the lack of densely eosinophilic layer, representing keratin, at the luminal side, in contrast with the earlier figure.
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